The present invention relates to 1,2-dihydropyrazol-3-ones which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 1,2-dihydropyrazol-3-ones and method for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.
Interleukin-1 (IL-1) and Tumor Necrosis Factor-xcex1 (TNF-xcex1) are among the important biological substances known collectively as xe2x80x9ccytokines.xe2x80x9d These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states.
There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them
The present invention meets the aforementioned needs in that it has been surprisingly found that certain bicyclic pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula: 
wherein R is:
a) xe2x80x94O[CH2]nR4; or
b) xe2x80x94NR5aR5b;
R4 is substituted or unsubstituted C1-C10 linear, branched, or cyclic alkyl; substituted or unsubstituted aryl; substituted or unsubstituted heterocyclic; or substituted or unsubstituted heteroaryl; the index n is from 0 to 5;
R5a and R5b are each independently:
a) hydrogen; or
b) xe2x80x94[C(R6aR6b)]mR7;
each R6a and R6b are independently hydrogen, xe2x80x94OR8, xe2x80x94N(R8)2, xe2x80x94CO2R8, xe2x80x94CON(R8)2; C1-C4 linear, branched, or cyclic alkyl, and mixtures thereof; R7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; xe2x80x94OR8, xe2x80x94N(R8)2, xe2x80x94CO2R8, xe2x80x94CON(R8)2; R8 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5;
R1 is substituted phenyl;
each R2 and R3 unit is independently selected from the group consisting of:
a) hydrogen; and
b) substituted or unsubstituted C1-C10 hydrocarbyl selected from the group consisting of:
i) C1-C10 linear, branched or cyclic alkyl;
ii) C6-C10 aryl;
iii) C1-C10 heterocyclic;
iv) C1-C10 heteroaryl.
Another aspect of the present invention relates to pharmaceutical compositions which can deliver the compounds of the present invention to a human or higher mammal, said compositions comprising:
a) an effective amount of one or more of the compounds according to the present invention; and
b) one or more pharmaceutically acceptable excipients.
A further aspect of the present invention relates to methods for controlling one or more inflammatory cytokine mediated or inflammatory cytokine modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal and effective amount of a composition comprising one or more of the compounds according to the present invention.
Another aspect of the present invention relates to forms of the compounds of the present invention, which under normal physiological conditions, will release the compounds as described herein.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0 C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
The present invention relates to compounds which are capable of mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes.
For the purposes of the present invention the term xe2x80x9chydrocarbylxe2x80x9d is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various unsubstituted non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]-heptan-1-yl, and naphth-2-yl.
Included within the definition of xe2x80x9chydrocarbylxe2x80x9d are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexane, cyclohexenyl, cycloheptanyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
The term xe2x80x9cheterocyclexe2x80x9d includes both aromatic (heteroaryl) and non-aromatic heterocyclic (heterocyclic) rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.
An example of a unit defined by the term xe2x80x9calkylenearylxe2x80x9d is a benzyl unit having the formula: 
whereas an example of a unit defined by the term xe2x80x9calkyleneheteroarylxe2x80x9d is a 2-picolyl unit having the formula: 
The term xe2x80x9csubstitutedxe2x80x9d is used throughout the specification. The term xe2x80x9csubstitutedxe2x80x9d is defined herein as xe2x80x9cencompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also substituted can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit.xe2x80x9d For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. An epoxide unit is an example of a substituted unit which requires replacement of a hydrogen atom on adjacent carbons. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as xe2x80x9csubstitutedxe2x80x9d any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a xe2x80x9csubstituted aromatic carbocyclic ringxe2x80x9d, (N,N-dimethyl-5-amino)octanyl is a xe2x80x9csubstituted C8 alkyl unit, 3-guanidinopropyl is a xe2x80x9csubstituted C3 alkyl unit,xe2x80x9d and 2-carboxypyridinyl is a xe2x80x9csubstituted heteroaryl unit.xe2x80x9d The following are non-limiting examples of units which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as xe2x80x9csubstituted.xe2x80x9d
i) xe2x80x94[C(R13)2]p(CHxe2x95x90CH)qR13;
ii) xe2x80x94[C(R13)2]pC(Z)R13;
iii) xe2x80x94[C(R13)2]pC(Z)2R13;
iv) xe2x80x94[C(R13)2]pC(Z)CHxe2x95x90CH2;
v) xe2x80x94[C(R13)2]pC(Z)N(R13)2;
vi) xe2x80x94[C(R13)2]pC(Z)NR 13N(R13)2;
vii) xe2x80x94[C(R13)2]pCN;
viii) xe2x80x94[C(R13)2]pCNO;
ix) xe2x80x94[C(R13)2]pCF3, xe2x80x94[C(R13)2]pCCl3, xe2x80x94[C(R13)2]pCBr3;
Z) xe2x80x94[C(R13)2]pN(R13)2;
xi) xe2x80x94[C(R13)2]pNR13CN;
xii) xe2x80x94[C(R13)2]pNR13C(Z)R13;
xiii) xe2x80x94[C(R13)2]pNR13C(Z)N(R13)2;
xiv) xe2x80x94[C(R13)2]pNHN(R13)2;
xv) xe2x80x94[C(R13)2]pNHOR13;
xvi) xe2x80x94[C(R13)2]pNCS;
xvii) xe2x80x94[C(R13)2]pNO2;
xviii) xe2x80x94[C(R3)2]pOR13;
xix) xe2x80x94[C(R13)2]pOCN;
xx) xe2x80x94[C(R13)2]pOCF3, xe2x80x94[C(R13)2]pOCCl3, xe2x80x94[C(R13)2]pOCBr3;
xxi) xe2x80x94[C(R13)2]pF, xe2x80x94[C(R13)2]pCl, xe2x80x94[C(R13)2]pBr, xe2x80x94[C(R13)2]pI, and mixtures thereof;
xxii) xe2x80x94[C(R13)2]pSCN;
xxiii) xe2x80x94[C(R13)2]pSO3M;
xxiv) xe2x80x94[C(R13)2]pOSO3M;
xxv) xe2x80x94[C(R13)2]pSO2N(R13)2;
xxvi) xe2x80x94[C(R13)2]pSO2R13;
xxvii) xe2x80x94[C(R13)2]pP(O)H2;
xxviii) xe2x80x94[C(R13)2]pPO2;
xxix) xe2x80x94[C(R13)2]pP(O)(OH)2;
xxx) and mixtures thereof;
xe2x80x83wherein R13 is hydrogen, substituted or unsubstituted C1-C20 linear, branched, or cyclic alkyl, C6-C20 aryl, C7-C20 alkylenearyl, and mixtures thereof; M is hydrogen, or a salt forming cation; Z is xe2x95x90O, xe2x95x90S, xe2x95x90NR13, and mixtures thereof; p is from 0 to 12; q is from 0 to 12. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like.
1,2-Dihydrodrvrazol-3-ones
The present invention relates to 1,2-dihydropyrazol-3-ones which inhibit the extracellular release of inflammatory cytokines. The compounds of the present invention comprise three elements. The first is the core 1,2-dihydropyrazol-3-one ring scaffold which can be substituted or unsubstituted as described herein below at the nitrogen atoms that comprise the ring system 1-position and 2-position. The second element is the 5-position pyrimidine ring attached at the 4-position of the pyrimidine ring and further substituted at the pyrimidine ring 2-position by either an ether group or an amino group. The third element is a substituted phenyl group at the ring scaffold 4-position. The following is a description of the compounds comprising the present invention.
R is a substituent at the 2-position of the pyrimidin-4-yl portion of the general scaffold, said R unit is:
a) an ether having the formula xe2x80x94O[CH2]nR4; or
b) an amino unit having the formula xe2x80x94NR5aR5b;
xe2x80x83wherein R4 is substituted or unsubstituted C1-C10 linear, branched, or cyclic alkyl; substituted or unsubstituted C6-C10 aryl; substituted or unsubstituted C1-C10 heterocyclic; or substituted or unsubstituted C1-C10 heteroaryl; the index n is from 0 to 5.
The following are the various aspects of R units according to the present invention wherein R is an ether having the formula xe2x80x94O[CH2]nR4. However, the formulator is not limited to the herein exemplified iterations and examples.
A) R units encompassing ethers having the formula xe2x80x94OR4 (the index n equal to 0) and R4 is substituted or unsubstituted aryl.
i) One iteration of this aspect of R comprises ethers having the formula xe2x80x94OR4 and R4 is substituted or unsubstituted aryl. This iteration includes the following non-limiting example of R: phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-difluorophenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy, 2,4-trifluoromethyl phenoxy, and the like.
ii) Another iteration of this aspect of R comprises ethers having the formula xe2x80x94OR4 and R4 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: 2-methylphenoxy, 3-methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 4-ethylphenoxy, and the like.
iii) A further iteration of this aspect of R comprises ethers having the formula xe2x80x94OR4 and R4 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: (2-methyoxy)phenoxy, (3-methoxy)phenoxy, (4-methoxy)phenoxy, 3-[(N-acetyl)amino]phenoxy, 3-benzo[1,3]dioxol-5-yl, and the like.
B) R units encompassing ethers having the formula xe2x80x94OR4 (the index n equal to 0) and R4 is substituted or unsubstituted heteroaryl.
i) A first iteration of this aspect of R comprises ethers having the formula xe2x80x94OR4 and R4 is unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like.
ii) A second iteration of this aspect of R comprises ethers having the formula xe2x80x94OR4 and R4 is substituted heteroaryl. This iteration includes the following non-limiting examples: 2-aminopyrimidin-4-yl, and the like.
C) R units encompassing ethers having the formula xe2x80x94OCH2R4 (the index n equal to 1) and R4 is substituted or unsubstituted aryl.
i) A first iteration of this aspect of R comprises ethers having the formula xe2x80x94OCH2R4 and R4 is substituted or unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, 2-aminopyrimidin-4-yl, 4-aminopyrimidin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like.
ii) A second iteration of this aspect of R wherein R is an ether having the formula xe2x80x94OCH2R4 and R4 is substituted or unsubstituted alkyleneheteroaryl-aryl. This iteration includes the following non-limiting examples: pyridin-3-ylethyl, (2-methyl-2-pyridin-3-yl)ethyl, and the like.
D) R units encompassing ethers having the formula xe2x80x94OR4 (the index n equal to 1) and R4 is substituted or unsubstituted C1-C4 alkyl or a C3-C10 carbocyclic unit.
i) A first iteration of this aspect of R is an ether having the formula xe2x80x94OR4 and R4 is unsubstituted C1-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: methyl, ethyl, isopropyl, (S)-1-methypropyl, and the like.
ii) A second iteration of this aspect of R is an ether having the formula xe2x80x94OR4 and R4 is a substituted C1-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: 2-methoxyethyl, (S)-1-methy-3-methyoxypropyl, and the like.
iii) A third iteration of this aspect of R is an ether having the formula xe2x80x94OR4 and R4 is a substituted or unsubstituted C3-C10 carbocyclic unit. This iteration includes cyclopropyl, cyclopentyl, 2,5-dimethylcyclopentyl, cyclohexyl, and the like.
The following are non-limiting examples of the various aspects of R units according to the present invention wherein R comprises an amino unit having the formula: 
wherein R5a and R5b are each independently:
a) hydrogen; or
b) xe2x80x94[C(R6aR6b )]mR7;
each R6a and R6b are independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl, xe2x80x94OR8, xe2x80x94N(R8)2, xe2x80x94CO2R8, xe2x80x94CON(R8)2; and mixtures thereof; R7 is hydrogen substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; xe2x80x94OR8, xe2x80x94N(R8)2, xe2x80x94CO2R8, xe2x80x94CON(R8)2; R8 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5. However, the formulator is not limited to the following exemplified iterations and examples.
A) R units encompassing racemic amino groups wherein R5a is hydrogen, R6a or R6b is hydrogen or C1-C4 alkyl, and R7 is substituted or unsubstituted aryl or heteroaryl, said units having the formula: 
i) A first iteration of this aspect includes units wherein both R6a and R6b are each hydrogen and R7 is aryl or substituted aryl, said units having the formula: 
xe2x80x83Non-limiting examples of this iteration include benzylamino, (4-fluorobenzyl)amino, (2-amino-benzyl)amino, (2-methylbenzyl)amino, (4-methylbenzyl)amino, (4-methoxybenzyl)amino, (4-methanesulfonyl)benzylamino, and (4-propanesulfonyl)benzylamino.
ii) A second iteration of this aspect includes units wherein one unit of R6a and R6b is hydrogen and the other is methyl, R7 is aryl or substituted aryl, said unit having the formula: 
xe2x80x83Non-limiting examples of this iteration include (xcex1)-methylbenzylamino, and 1-(4-fluorophenyl)-ethylamino.
iii) A third iteration of this aspect includes units wherein both R6a and R6b are each hydrogen and R7 is heteroaryl or substituted heteroaryl. Non-limiting examples of this iteration include (pyridin-2-yl)methylamino, (pyridin-3-yl)methylamino, (pyridin-4-yl)methylamino, and (imidazol-2-yl)methylamino.
B) R units encompassing racemic amino groups wherein R5a is hydrogen, R6a or R6b is hydrogen or C1-C4 alkyl, and R7 is substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, said units having the formula: 
i) A first iteration of this aspect includes units wherein both R6a and R6b are each hydrogen and R7 is hydrogen or C1-C6 linear, branched, or cyclic alkyl. 
xe2x80x83Non-limiting examples of this iteration include methylamino, ethylamino, propylamino, isobutylamino, and cyclopropylmethylamino.
ii) A second iteration of this aspect includes units wherein one unit of R6a and R6b is hydrogen and the other is methyl, and R7 is hydrogen or C1-C6 linear, branched, or cyclic alkyl. 
xe2x80x83Non-limiting examples of this iteration include isopropylamino, and sec-butylamino.
iii) A third iteration of this aspect includes units wherein both R6a and R6b are each hydrogen and R7 is substituted C1-C6 linear, branched, or cyclic alkyl. Non-limiting examples of this iteration include 2-methoxyethylamino, and 2-methoxy-2-methylpropylamino.
iv) A fourth iteration of this aspect includes units wherein one unit of R6a and R6b is hydrogen and the other is methyl, and R7 is substituted C1-C6 linear, branched, or cyclic alkyl. Non-limiting examples of this iteration include 1-methyl-2-methoxyethylamino, and 1,2-dimethyl-2-methoxyethylamino.
C) R units encompassing racemic amino groups wherein R5a is hydrogen, R6a or R6b is hydrogen or xe2x80x94CO2R8; R8 is hydrogen or methyl; and R7 is hydrogen or substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; said units having the formula: 
i) A first iteration of this aspect includes units which are derived from alkyl unit comprising amino acids and amino acid methyl esters. Non-limiting examples of this iteration include carboxymethylamino (from glycine), (carboxymethyl)methylamino (from glycine methylester), and 1-(carboxy)ethylamino (from alanine).
ii) A second iteration of this aspect includes units which are derived from substituted or unsubstituted aryl unit comprising amino acids and amino acid methyl esters. Non-limiting examples include (xcex1)-carboxybenzylamino (from phenylalanine) and 1-carboxy-2-(4-hydroxyphenyl)ethylamino (from tyrosine).
D) R units encompassing chiral amino groups wherein R5a is hydrogen, R6a is hydrogen, R6b is C1-C4 alkyl, and R7 is substituted or unsubstituted aryl or heteroaryl, said units having the formula: 
xe2x80x83with the indicated stereochemistry.
i) A first iteration of this aspect includes units wherein R6b is methyl, R7 is aryl or substituted aryl. Non-limiting examples of this iteration include (S)-(xcex1)-methylbenzylamino, (S)-1-methyl-1-(4-fluorophenyl)methylamino, (S)-1-methyl-1-(2-aminophenyl)methylamino, (S)-1-methyl-1-(2-methylphenyl)methylamino, (S)-1-methyl-1-(4-methylphenyl)methylamino, and (S)-i -methyl-1-(4-methoxyphenyl)-methylamino.
ii) A second iteration of this aspect includes units wherein R6b is ethyl or hydroxyethyl, R7 is aryl or substituted aryl. Non-limiting examples of this iteration include (S)-(xcex1)-ethylbenzylamino, (S)-1-(4-fluorophenyl)ethylamino, (S)-1-(2-aminophenyl)-ethylamino, (S)-1-ethyl-1-(2-methylphenyl)amino, (S)-1-(4-methylphenyl)-ethylamino, (S)-1-(4-methoxyphenyl)ethylamino, and (S)-1-(4-fluorophenyl)-2-hydroxyethylamino.
E) R units encompassing chiral amino groups wherein R5a is hydrogen, R6a is hydrogen, R6b is C1-C4 alkyl, and R7 is substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, said units having the formula: 
xe2x80x83with the indicated stereochemistry.
i) A first iteration of this aspect includes units wherein R6b is methyl and R7 is C1-C6 linear, branched, or cyclic alkyl. Non-limiting examples of this iteration include (S)-1-methylpropylamino, (S)-1-methyl-1-methoxyethylamino, (S)-1-methyl-2-(S)-methoxypropylamino, (S)-1,2-dimethyl-2-hydroxypropylamino, and (S)-1,2-methyl-2-methoxypropylamino.
ii) A second iteration of this aspect includes units wherein R6b is C2-C4 alkyl and R7 is C1-C6 linear, branched, or cyclic alkyl. Non-limiting examples of this iteration include (S)-1-ethylpropylamino, (S)-1-ethyl-1-methoxyethylamino, (S)-1-ethyl-2-(S)-methoxypropylamino, and (S)-1-ethyl-2-methyl-2-methoxypropylamino.
F) R units encompassing chiral amino groups wherein R5a is hydrogen, R6a or R6b is hydrogen or xe2x80x94CO2R8; R8 is hydrogen or methyl; and R7 is hydrogen or substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; said units having the formula: 
xe2x80x83with the indicated stereochemistry.
i) A first iteration of this aspect includes R units which are derived from aryl unit comprising amino acids and amino acid methyl esters, said units having the formula: 
xe2x80x83wherein R8 is hydrogen or methyl. Non-limiting examples include (S)-(xcex1)-carboxybenzylamino (R unit derived from L-phenylglycine).
ii) A second iteration of this aspect includes units which are derived from substituted or unsubstituted alkyl unit comprising amino acids and amino acid methyl esters. Non-limiting examples of this iteration include 1-(S)-(carboxy)ethylamino (from L-alanine).
R1 is substituted phenyl. The units may be substituted by any xe2x80x9csubstituentxe2x80x9d group described herein above.
The first aspect of R1 units relates to halogen substituted phenyl, for example, 4-fluorophenyl 2,4-difluorophenyl, 4-chlorophenyl, and the like. A second aspect relates to methyl substituted phenyl, for example, 3-methylphenyl and 4-methylphenyl. A third aspect relates to trifluoromethyl ring substituents, non-limiting examples of which include 3-trifluoromethylphenyl.
Each R2 and R3 unit is independently selected from:
a) hydrogen; and
b) substituted or unsubstituted C1-C10 hydrocarbyl selected from:
i) C1-C10 linear, branched or cyclic alkyl;
ii) C1-C10 aryl;
iii) C1-C10 heterocyclic;
iv) C1-C10 heteroaryl.
Among the definitions of cyclic alkyl, aryl, heterocyclic, and heteroaryl as it relates to the R2 and R3 units of the present invention, are included rings formed from functional groups and rings attached to the 1,2-dihydropyrazol-3-one ring scaffold by a tether. The tether is typically one or more alkylene units. These units include:
a) xe2x80x94(CH2)jR9;
b) xe2x80x94(CH2)jNR10aR10b;
c) xe2x80x94(CH2)jCON(R11)2;
d) xe2x80x94(CH2)jOCON(R11)2;
e) and mixtures thereof;
xe2x80x83wherein R9 is a cyclic ether unit, inter alia, pyranyl and furanyl; R10a and R10b or two R11 units are taken together to form a heterocyclic or heteroaryl unit comprising from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5.
The first aspect of R2 and R3 relates to 1,2-dihydropyrazol-3-one ring scaffolds wherein both R2 and R3 are each hydrogen. One iteration includes the generic compounds encompassed by 4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one.
The second aspect of R2 and R3 relates to 1,2-dihydropyrazol-3-one ring scaffolds wherein R2 is a substituted or unsubstituted heterocyclic ring and R3 is a substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl unit. One iteration includes the generic compounds encompassed by 1-(piperidin-4-yl)-2-methyl-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one.
The third aspect of R2 and R3 relates to 1,2-dihydropyrazol-3-one ring scaffolds wherein R2 is a substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl unit and R3 is a substituted or unsubstituted heterocyclic ring. One iteration includes the generic compounds encompassed by 1-methyl-2-(piperidin-4-yl)-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one.
Non-limiting examples of the second and third aspects of R2 and R3 units encompass the substituted and unsubstituted rings, inter alia, scaffolds having the formula: 
and R12 is xe2x80x94[C(R13)2]pC(O)2R13, non-limiting examples of which include xe2x80x94(CH2)CO2H, xe2x80x94(CH2)CO2CH3, xe2x80x94[CH(CH3)]CO2H, xe2x80x94[CH(CH3)]CO2CH3, xe2x80x94[C(CH3)2]CO2H, xe2x80x94[C(CH3)2]CO2CH3, or the water soluble salts of the acids.
The fourth aspect of R2 and R3 relates to 1,2-dihydropyrazol-3-one ring scaffolds wherein R2 and R3 are each independently C1-C6 alkyl. One iteration of this aspect relates to rings wherein R2 and R3 units are the same, interalia, the generic compounds 1,2-dimethyl-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one and 1,2-diethyl-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one.
However, other non-exemplified aspects include compounds, inter alia, under the generic formulae 1-substituted aryl-2-(piperidin-4-yl)-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one, 1-(morpholin-4-yl)-2-(heteroaryl)-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one, and 1-heteroaryl-2-substitued aryl-4-(R1)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one.
Selection of R2 and R3 units and combinations thereof directly relate to the Categories described herein below. For example, compounds wherein both R2 and R3 are each methyl, ethyl, or other lower alkyl, relates to Category IV analogs.
The analogs (compounds) of the present invention are arranged in several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
The analogs (compounds) of the present invention are conveniently obtained in the salt form, for example, the trifluoroacetate salt, especially after removal of protecting groups with trifluoroacetic acid as the last step in their preparation. However, the formulator may neutralize the analogs, or convert them to another salt form without change to the efficacy of the parent compounds. Also, the formulator, if convenient or practicable, will prepare a pro-drug which will release the active compound (analog) upon uptake by the host. All of these variations are encompassed within the present invention.
The first category of inflammatory cytokine release inhibiting compounds according to the present invention are 4-R1-substituted-5-(2-R-substituted-pyrimidin-4-yl)-1,2-dihydropyrazol-3-ones having the general scaffold with the formula: 
wherein the first aspect of Category I has the formula: 
R1 and R4 are described herein below in Table I. The index n can be 0 or 1.
The analogs 1-48 are non-limiting examples of analogs which comprise the first aspect of Category I. The analogs of the first aspect of Category I can be suitably prepared by the procedure outlined herein below. In the following example, R1 is 4-fluorophenyl, however, the formulator may suitably substitute any starting material compatible with this procedure, inter alia, methyl phenylacetate, methyl 4-chlorophenylacetate, and methyl 3-(trifluoromethyl)phenylacetate. 